Association between exposure to air pollutants and hospitalization for SARS-Cov-2: an ecological time-series study

ABSTRACT BACKGROUND: Exposure to air pollutants and illness by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection can cause serious pulmonary impairment. OBJECTIVE: To identify a possible association between exposure to air pollutants and hospitalizations due to SARS-Cov-2. DESIGN AND SETTING: Ecological time-series study carried out in Taubaté, Tremembé, and Pindamonhangaba in 2020 and 2021. METHODS: Study with Sars-Cov-2 hospitalizations with information on hospitalization date, sex and age of the subjects, duration of hospitalization, type of discharge, and costs of these hospitalizations. Statistical analysis was performed through a negative binomial regression, with data on pollutant concentrations, temperature, air relative humidity, and hospitalization date. Coefficients obtained by the analysis were transformed into relative risk for hospitalization, which estimated hospitalizations excess according to an increase in pollutant concentrations. RESULTS: There were 1,300 hospitalizations and 368 deaths, with a predominance of men (61.7%). These data represent an incidence rate of 250.4 per 100,000 inhabitants and 28.4% hospital lethality. Significant exposure (P value < 0.05) occurred seven days before hospital admission (lag 7) for nitrogen dioxide (NO2) (relative risk, RR = 1.0124) and two days before hospital admission for PM2.5 (RR = 1.0216). A 10 μg/m3 in NO2 concentration would decrease by 320 hospitalizations and » US $ 240,000 in costs; a 5 μg/m3 in PM2.5 concentration would decrease by 278 hospitalizations and » US $ 190,000 in costs. CONCLUSION: An association between exposure to air pollutants and hospital admission due to Sars-Cov-2 was observed with excess hospitalization and costs for the Brazilian public health system.


INTRODUCTION
The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a global pandemic first detected in Wuhan, China, in December 2019. 1 COVID-19 is a highly transmissible and fatal syndrome-induced disease, followed by severe acute respiratory disease.
Typically, COVID-19 infected patients show mild to moderate symptoms, including sore throat, fever, shortness of breath, dry cough, and loss of smell and taste, while it causes pneumonia with severe acute respiratory syndrome (SARS), kidney failure, and even death in some patients. 2,3 Initially described in December 2019 in Wuhan City, capital of China's Hubei Province, it became the center of an outbreak of pneumonia of unknown cause. In January 2020, scientists isolated a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-nCoV. 4 Exposure to air pollutants has been linked to hospitalizations, respiratory diseases, cardiovascular diseases, and death. [5][6][7][8] However, studies have been carried out associating air pollution, and hospitalizations, and deaths from COVID-19; other studies have shown the interrelationship of short-term and chronic exposure to ambient air pollution and COVID-19 infection. 9,10 Among these pollutants is nitrogen dioxide (NO 2 ), a nitrogen-centered free radical mainly produced in urban areas by traffic. Ozone (O 3 ) is a secondary atmospheric pollutant composed of three oxygen atoms formed at ground level by NO 2 reactions and volatile organic compounds with sunlight.
Particulate matter is a mixture of liquid, solid, or solid and liquid particles suspended in the air and is composed of a carbonaceous core of organic compounds (polycyclic aromatic hydro-

OBJECTIVE
This study aimed to identify possible associations between exposure to air pollutants and hospitalizations due to COVID-19 in residents of the conurbation cities of Taubaté, Tremembé, and Pindamonhangaba, SP, given the fact that exposure to air pollutants is associated with diseases of the respiratory system and COVID-19 is a respiratory system's disease.

METHODS
An ecological time-series study was carried out with data on hos- addition to data of daily temperature and relative humidity, and a correlation matrix was built with these variables. Poisson's probability distribution is the closest to the frequency of hospitalizations since it involves discrete and counting data, with an excess of zeros and asymmetric and asymptotic distribution; however, these data may have a different mean from the variance and, for this reason, the multivariate model of negative binomial regression was used.
A multipollutant model with a confidence interval of 95% was used for the analyses, in addition to a lag period of 0 to 7 days (lag 0-7) because the effect of pollutants can be felt days after exposure. The chance of death (OR) according to sex was calculated with a confidence interval of 95%. Student's t-test was used; to compare the mean age and length of stay according to sex and type of discharge -death or alive; alpha = 0.05 was the significance level adopted in this study. (P value = 0.23), and it can be seen in Table 1.
These data represent an incidence rate of 250.4 cases per 100,000 inhabitants and hospital lethality of 28.4%.
The length of stay of patients hospitalized for SARS-CoV-2 who died had an average of 12.3 (± 10.9) days, while in hospitalizations that were discharged, it was 8.5 days (± 9.3) (P value < 0.01). Analyzing hospitalizations that resulted in death, the mean age was 67.6 years (± 13.6), while the mean age of patients who were discharged was 56.8 years (± 16.6) (P value < 0.01), demonstrating that older patients are more likely to die when hospitalized.  Table 2. The values provided by Pearson's correlation matrix for the study variables are in Table 3.
The daily values of cases, as well as the values of significant concentrations of air pollutants found in the study period, are shown in Figures 1-A, 1-B, and 1-C.     Both hospitalizations that were discharged and hospitalizations that led to death generated costs of approximately R$ 8 million (≈ US$ 1.6 million); hospitalizations that required intensive care were responsible for 65% of the costs, and hospitalizations that resulted in death were responsible for R$ 4.5 million (≈ 51% of the total).
The costs presented correspond to the hospitalizations from April 2020 to March 2021. per 100,000 inhabitants; these values, well above those found in our study, may be associated with geographic differences and differences in the source of data collection. Males had a higher prevalence of hospitalizations and deaths than females, which was similar to the findings of our study. 15 The same behavior was found by Peres et al. 16 and Klokner et al. 17 This relatively unequal incidence and mortality in men can be interpreted considering many factors: the comparatively higher prevalence of comorbidities (hypertension, diabetes, cardiovascular diseases, and chronic lung diseases), more risk behaviors (smoking and alcohol use), and exposure to occupational and sex differences in immune responses. 18,19 In a study carried out in India, where the concentrations of PM 2.5 were 88.3 ug/m 3 and those of NO 2 , 36.5 ug/m 3 , associations were also identified between exposure to these pollutants and new cases of COVID-19 as well as an association with new deaths. 20 Daily confirmed cases in 120 Chinese cities were obtained from January 23, 2020, to February 29, 2020, where significantly positive associations were observed for PM 2.5 and NO 2 exposure. A 10 μg/m 3 (lag 0-14) increase in PM 2.5 and NO 2 was associated with 2.24% (95% CI: 1.02 to 3.46) and 6.94% (95% CI: 2.38 to 11.51) in the daily count of confirmed cases, respectively. 21 In two regions of northern Italy, with tropospheric nitrogen data estimated by satellite, even with low model accuracy, it was possible to identify an association between high concentrations of NO 2 and deaths from COVID-19, which provides evidence supporting a pollution effect in increasing the proportion of fatal cases of the disease. The association was stronger when using the longer-term cumulative mortality as an outcome. 22 Another important data revealed in this study is the cost of these hospitalizations. Hospitalizations that resulted in hospital discharge cost R$ 3,526,328.67, and the hospital cost for patients who died cost R$ 4,538,663.57; hospitalizations that resulted in death and that required intensive care (ICU) cost twice as much as those that resulted in ICU discharge.

Relative risk index values can be seen in
If they reduced 5 μg/m 3 of the pollutant PM 2.5 in the atmosphere and 10 μg/m 3 of the pollutant NO 2 , in the case of the studied region, the savings could be up to R$ 1.2 million.
The mechanisms involved are still poorly understood. It is believed that increased oxidative stress is the key mechanism of pollutant-induced toxicity and that PM 2.5 suspended in the atmosphere would facilitate viral survival and promote its atmospheric transport. Exposure to air pollutants promotes viral entry, replication, and assembly, which cause increased local inflammation due to reduced mucociliary clearance, modulation of cellular pathways, and increased epithelial permeability because of decreased junction proteins with a substantial increase in viral spread and inflammation due to permeable epithelium, prevention of macrophage uptake and defects in natural killer (NK) cell functions with amplification of inflammation and neutrophil recruitment plus increased virus-induced tissue damage and inflammation.
This sequence of events leads to fluid accumulation in the alveoli, respiratory failure, and death. 23 This study had limitations. First, due to ecological studies, the type of information obtained from an official source might have a diagnostic error. Second, the address of the subject who informed it possibly wrongly. Third, lack of information on co-morbidities might have contributed to the impossibility of assessing the importance of risk factors mentioned in the literature and estimating their importance in the number of cases. Moreover, exposure to pollutants might not be indicated as a cause of infection by COVID-19, but an association between exposure and cases.

CONCLUSION
Regardless of what might have caused the possible abovementioned limitations, it was possible to identify an association between exposure to PM 2.5 and NO 2 pollutants in hospitalizations due to COVID-19, in addition to the total cost of these hospitalizations.